Phenyl-benzodioxane derivatives

ABSTRACT

6-Phenyl-1,3-benzodioxan-4-one derivatives and 6-phenyl-1,3benzodioxane derivatives and methods of preparing these compounds. The primary methods for preparing the aforementioned benzodioxane-ketone compounds are characterized by the step of treating the corresponding 2-hydroxy-5-phenyl benzoic acid derivative with an alkyl ortho-ester in the presence of an acid catalyst. The primary methods for preparing the 6-phenyl-1,3benzodioxane derivatives are characterized by the step of treating the corresponding 2-hydroxy-5-phenyl benzyl alcohol with a ketone or aldehyde in the presence of an acid catalyst. The aforementioned phenyl-1,3-benzodioxan-4-one derivatives and 6phenyl-1,3-benzodioxane derivatives have analgesic activity and thus are useful in the treatment of mammals wherein analgesics are indicated.

United States Patent [191 Fried [111 3,741,985 [451 June 26, 1973PHENYL-BENZODIOXANE DERIVATIVES John H. Fried, Palo Alto, Calif.

[73] Assignee: Syntex Corporation, Panama,

Panama [22] Filed: Jan. 21, 1971 [21] App]. No.: 108,609

[75] Inventor:

[52] U.S. Cl. 260/3402, 260/340.3, 260/473 S, 260/520, 260/332.3 P,260/999 Primary Examiner-Norma S. Milestone Att0rneyEvelyn K. Merker,Gerard A. Blaufarb and Lawrence S. Squires [5 7] ABSTRACT6-Phenyl-l,3-benzodioxan-4-one derivatives and 6-phenyl-l,3-benzodioxane derivatives and methods of preparing these compounds.The primary methods for preparing the aforementioned benzodioxane-ketonecompounds are characterized by the step of treating the corresponding2-hydroxy-5-phenyl benzoic acid derivative with an alkyl ortho-ester inthe presence of an acid catalyst. The primary methods for preparing the6-phenyl-1,3-benzodioxane derivatives are characterized by the step oftreating the corresponding 2- hydroxy-S-phenyl benzyl alcohol with aketone or aldehyde in the presence of an acid catalyst. Theaforementioned phenyl-l,3-benzodioxan-4-one derivatives and6-phenyl-l,3-benzodioxane derivatives have analgesic activity and thusare useful in the treatment of mammals wherein analgesics are indicated.

9 Claims, No Drawings PHENYL-BENZODIOXANE DERIVATIVES BACKGROUND OF THEINVENTION 1. The Invention This invention relates to6-phenyl-1,3-benzodioxane derivatives and to methods of preparing suchderivatives. In a further aspect, this invention relates to 6-phenyl-l,3-benzodioxane derivatives and 6-phenyll,3-benzodioxan-4-onederivatives, substituted at the 2 and/or 4 positions and to methods'ofpreparing such compounds. In a still further aspect this inventionrelates to 4-halo derivatives of 6-phenyl-l,3- benzodioxane and6-phenyl-1,3-benzodioxan-4-one derivatives which are further substitutedat the 2-position, and to methods of preparing such compounds. Inanother aspect, this invention relates to means for carrying out theafore-mentioned methods and to methods and means for administering theaforementioned compounds of my invention.

2. The Prior Art At the present time, one of the most widely usedcompounds for alleviating or mitigating pain and fever isacetylsalicylic acid, commonly known as aspirin. This compound has innormal dosage ranges a relatively low toxicity and a relatively lowincidence of adverse side effects. There is, however, a tendency in somepatients, even where normal dosage ranges are used, to developindigestion, heartburn, and other forms of gastric irritation, and wherehigher dosage ranges are required, the gastric effect may beprohibitive, resulting, in some instances, in gastric hemorrhage.Accordingly, I have developed a new group of compounds having highanalgesic and anti-pyretic activity, and also anti-inflammatoryactivity, but without the adverse gastric effect incident to aspirin.

Phenyl salicyclic acid compounds purported to have anti-inflammatoryactivity effective in the prevention and inhibition of edema andgranuloma tissue formation, and further purported to have some degree ofanti-pyretic and analgesic activity are also known to the art; see, forexample, Canadian Patent Nos. 799,516 and 818,560.

SUMMARY In summary, the compounds of my invention can be represented bythe following generic formula:

wherein R is H, lower alkyl, lower alkoxy, fluoro, chloro, bromo, iodo,or trifluoromethyl; and Z is the group OR or the group R 30 3O atoms, ora saturated monocyclic monoheterocyclic group having five or six ringatoms and having only one non-carbon ring atom, which non-carbon ringatom is selected from the group consisting of oxygen and sulfur.

The 2-lower alkoxy compounds of my invention can, in summary, beprepared according to the methods of my invention by treating thecorresponding 2-hydroxy-5-phenyl-benzoic acid or -benzyl alcoholderivatives with a suitable alkyl ortho-ester in the pres- DETAILEDDESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS The compounds ofmy invention can be conveniently represented by the following subgenericformulas:

v gab R1 R ix foil 0 8&0 Ra R 8 1X wherein R is H, lower alkyl, loweralkoxy, fluoro, chloro, bromo, iodo, or trifluoromethyl; R is H or loweralkyl, R is lower alkyl, R is selected from the group consisting of H,lower alkyl, and lower alkoxy; R is selected from the group consistingof H and lower alkyl or R and R together with the carbon atom to whichthey are joined form a cyclic alkyl group having from five through sevenring carbon atoms, or a saturated monocyclic monoheterocyclic grouphaving 5 or 6 ring atoms containing only one non-carbon ring atom, saidnon-carbon ring atom being selectedfrom,

the group consisting of oxygen and sulfur.

As used hereinabove and below, the following terms have the followingmeanings. The term lower alkyl refers to alkyl groups having from onethrough seven carbon atoms and includes both straight chained andbranched chain alkyl groups. Typical lower alkyl groups thus include,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, and the like. The term lower alkoxy refers to alkoxy groupshaving from one through seven carbon atoms. Typical lower alkoxy groupsinclude, for example, methoxy, ethoxy,

' isopropoxy, and the like. The term cyclic alkyl group refers to cyclicalkyls having from five to seven ring carbon atoms, which ring carbonatoms may be substituted or unsubstituted. Typical cyclic alkyl groupsthus include, for example, cyclopentyl, cyclohexyl, cy-

benzodioxane; 6-( 4 'fluorophenyl)-2,2-diisopropyl-l ,3-

benzodioxane; 6-(4'-chlorophenyl)-2,2-diisopropyl-1 ,3-

benzodioxane; 2,2-diisopropyl-6-( 4-trifluoromethylphenyl l ,3-

benzodioxane; 2-ethyl-6-(4-fluorophenyl)-2-n-hexyl- 1 ,3-

benzodioxane; 6-(4-fluorophenyl l ,3-benzodioxane-2-spirocyclohexane;6-(4'-chlorophenyl)-l ,3-benzodioxane-2-spirocyclohexane;

6-(4-trifluoromethylphenyl)- l ,3-benzodioxane-2- spiro-cyclohexane;6-(4-fluorophenyl)-l ,3-benzodioxane-2-spiro-3 tetra hydrothiophene;6-(4'-chlorophenyl)-l ,3-benzodioxane-2-spiro-3 tetra hydrothiophene;6-(4-trifluoromethylphenyl)-l ,3-benzodioxane-2- spiro-3-tetrahydrothiophene; 6-(4'-f1uorophenyl)- l,3-benzodioxane-2-spirocyclopentane; 6-(4 -chlorophenyl)- l,3-benzodioxane-2-spirocyclopentane; 6-(4'trifluoromethylphenyl)-l,3-benzodioxane-2- spiro-cyclopentane; 6-(4'-fluorophenyl)- l,3-benzodioxane-2-spiro-l (4'-methylcycloheptane);6-(4-chlorophenyl)-1,3-benzodioxane-2-spiro-l (4-methylcycloheptane);6-(4'-trifluoromethylphenyl)-l ,3-benzodioxane-2- spiro-l'-(4'-methylcycloheptane); 6-(4-fluorophenyl)- l,3-benzodioxane-2-spiro-2'- tetra-hydrofuran; 6-( 4-chlorophenyl)-l,3-benzodioxane-2-spiro-2'- tetra-hydrofuran;6-(4-trifluoromethyiphenyD-l ,3-benzodioxane-2- Spiro-2-tetrahydrofuran;I 6-(4-fluorophenyl)-l ,3-benzodioxane-2-spiro-2'- tetra-hydropyran; 6-(4 '-chlorophenyl)-l ,3-benzodioxane-2-spiro-2- tetra-hydropyran; and 6-(4 -trifluoromethylphenyl l ,3-benzodioxane-2- spiro-2'-tetrahydropyran.Additional examples of typical compounds of my invention can be had byreference to the Examples.

The compounds of formulas II and III of my invention can be convenientlyprepared by treating the corresponding 2-hydroxy-6-phenyl-benzoic acidor 2-hydroxy-6-phenyl-benzyl alcohol derivative with a suitableorthoester in the presence of an acid catalyst. For purposes ofsimplicity, this treatment will be dis cussed hereinbelow with respectto the preparation of compounds of formula II, however, the procedure isequally applicable to the preparation of the 2-lower alkoxy compounds offormula III, but, of course, using 2-hydroxyphenyl-benzyl alcoholderivatives as starting materials.

This treatment can be represented by the following schematic overallreaction equation:

wherein R, R and R have the same meaning as set forth herein above.

This treatment can be conveniently effected by con-- tacting thecompounds of formulas (A) and (B) together, in the presence of an acidcatalyst, at temperatures in the range of about from 20 to C for aboutfrom one to 48 hours. However, treatment temperatures and times bothabove and below these ranges can also be used. Typically, longerreaction times will be used with lower reaction temperatures. Bestresults are obtained by conducting the treatment in benzene at reflux.Preferably the reagents are contacted together in the liquid state. Alsothe treatment can be optionally conducted in a suitable inert liquidorganic medium, which is preferably a solvent for at least one of thereactants. Suitable inert organic reaction media include, for example,benzene, toluene, tetrahydrofuran, diox-. ane, chloroform,dimethylformamide, carbon tetrachloride, methylene chloride and thelike. This reaction can be advantageously promoted by using an aromaticsolvent such as, for example, benzene, which facilitates the continuousremoval of the alcohol by-product via azeotropic distillation during thereaction. Alternatively, the reaction can be promoted by removing thealcohol by-product by refluxing,,or continuously passing a portion ofthe reaction mixture, through a selective, adsorbent, such as forexample calcium Type A (5A) or faujasite 13X (Type X and Y) zeolitemolecular sieves, which will selectively remove the alcohol byproductbecause of its effective dynamic molecular size or polarity. Thisadsorption separation, can be conveniently conducted on a laboratoryscale via the use of a soxhlet apparatus containing the desiredadsorbent.

Also a combination of azeotropic distillation andselective adsorptioncan also be used.

Typically, the treatment will be conducted using mole ratios in therange of about from one to 40 moles of alkyl orthoester per mole of2-hydroxy-6-phenylbenzoic acid-(formula-A starting materials, however,

mole ratios above this range can also be used. The resulting product offormula ll of my invention can be separated from the reaction mass byany suitable means, for example, the product can be convenientlyseparated by extraction with a suitable organic solvent followed byevaporation 'of the solvent and if desired, further purified byrecrystallization and/or chromatography.

Suitable acid catalysts include, for example, p-toluene-sulfonic acid,pyridine hydrochloride, perchloric acid, sulfuric acid, phosphoric acid,trifluoroacetic acid and the like. The alkyl orthoester startingmaterials of formula (B) are known materials and can be obtained fromknown sources or prepared according to known procedures such as, forexample, described in Org. Syn., Coll. Vol., (edited by Kaufmann andDreger) vol. 1, page 258 (1941) and cited in Wagner and Zook, SyntheticOrganic Chemistry, pages 542-545, Wiley 1963 Suitable alkyl orthoestersinclude, for example, triethylorthoformate, triethylorthoacetate,trimethylorthoacetate, trimethylorthopropionate,triethylorthopropionate, tripropylorthoformate, tripropylorthoacetate,tripropylorthopropionate, and the like. The 2hydroxy-Sphenyl-benzoicacid starting materials of formula (A) are also known materials and canbe obtained from known sources or prepared according to known proceduressuch as, for example, those described in Canadian Pats. No. 799,519;799,520; 799,521; 818,560; and Belgium Patent No. 703,499 or by theapplication of known procedures for adding the desired R substituentgroup to such procedures. For example,-(4-loweralkyl-phenyl)-2-hydroxy-benzoic acid starting materials can beobtained by treating 5-( 4- iodophenyl)-2-hydroxy,-benzoic acidaccording to the procedure ofCanadian Patent No. 799,520 to obtain5-(4-iodophenyl)-2-acetoxy-benzoic acid, which can in turn beesterified, according to conventional procedures to yield5-(4-iodophenyl)-2-acetoxy-methylbenzoate which in turn can be treatedwith lithium dialkyl copper to obtain 5-(4-loweralkyl-phenyl)-2-hydroxy-benzoic acid starting materials.

The starting materials of formula (D) can be obtained from known sourcesor can be prepared according to known procedures such as, for example,by reduction of the corresponding 2-hydroxy-5-phenylbenzoic acid(formula A) with lithium aluminum hydride. Alternatively, the compoundsof formula (D) can be prepared by the same general procedures as used toprepare the compounds of formula (A), such as for example, described inCanadian Patent No. 824,173, but coupling with o-hydroxymethylphenolstarting materials in place of o-hydroxy-benzoic acid startingmaterials.

This treatment can be schematically represented by the following overallreaction equation:

noon

Lewis acid catalyst wherein R and R are as defined herein above.

This treatment can be conveniently effected by contacting the reactantsof formulas (A) and (C) together, in the presence of a suitable Lewisacid catalyst. Typically, thetreatment is conducted at temperatures inthe range of about from to 20C, for about from one to 48 hours. However,temperatures and treatment times both above and below these ranges canalso be Typically, the mole ratio of reactants will be in the range ofabout from one to 40 moles of lower alkoxy alkyne (formula (C)) per moleof 2-hydroxy-5-pl1enylbenzoic acid (formula (A)), however, mole ratiosabove this can also be used. The lower alkoxy alkyne starting materialsof formula (C) are known compounds, having from three through 14 carbonatoms,

and can be obtained from known sources or prepared according to knownprocedures, note for example, Fieser & Fieser, Reagents for OrganicSynthesis, pp. 357-360 and 668, Wiley, New York (l967).Suitable loweralkoxy alkynes thus include, for example, methoxy acetylene; ethoxyacetylene; 3-methoxy-2- propyne; 3-ethoxy-2-propyne; 4-methoxy-3-butyne;4- ethoxy-3-butyne; 4-propoxy-3-butyne; 8-methoxy-7- octyne;8-ethoxy-7-octyne; 8-propoxy-7-octyne; 8-isopro-poxy-7-octyne;8-heptyloxy-7-octyne and the like.

The compounds of formula llLof my invention, with the exception of thosecompounds wherein R and R.

form an oxo heterocyclic ring, which are more conveniently preparedaccording to another method, of my invention, which will be subsequentlydescribed, can be conveniently prepared according to my invention bytreating the corresponding 2-hydroxy-5phenyl-benzyl alcohol compoundswith a suitable aldehyde, acetal,

ketone or ketal, as defined by formula (E) hereinbe f low.

This treatment can be schematically represented by the following overallreaction equation:

lt OH /C=R5 Acid eat.

R4 (3) CHaOH (D) (E) R" HaR 0 (Illa) wherein R and R are independentlyselected from the group consisting of H and lower alkyl, or togetherwith the carbon atom to which they are joined form a cyclic alkyl grouphaving from five through seven 'ring carbon atoms, or a thia monocyclicmonoheterocyclic group having five or six ring atoms, containing onlyone non-carbon ring atom, said noncarbon ring atom being sulfur; R isoxo or the group one wherein R and R are the same or different loweralkyls; and R is as defined herein above.

This reaction can be conveniently effected by contacting the reactantsof formulas (D) and (E) together at temperatures in the range of aboutfrom 20 to 80 for about from one to 48 hours, in the presence of asuitable acid catalyst. However, temperatures and treatment durationsboth above and below these ranges can also be used. Best results aretypically obtained by using the reflux temperature or temperaturesapproaching the reflux temperature. Preferably the reactants arecontacted together in the liquid state and typically are contacted in asuitable inert organic solvent. Suitable inert organic solvents include,for example, benzene, dimethylformamide, toluene, chloroform, methylenechloride, and the like. Suitable acid catalysts include, for example,p-toluenesulfonic acid, perchloric acid, pyridine hydrochloride,sulfuric acid, phosphoric acid, trifluoroacetic acid, and the like. Alsothis reaction can be advantageously promoted via use of the azeotropicdistillation and/or selective adsorption procedures previously describedhereinabove to remove the by-product water or alcohol.

The relative mole ratio of reactants is preferably in the range of aboutfrom one to 40 moles of compound of formula (E) per mole of the2-hydroxy-5-phenylbenzyl alcohol compound of formula (D). The compoundsof formula (E) are known compounds or can be prepared by knownprocedures, or obvious modifications thereof, to effect the desiredsubstituents. Typical procedures for preparing such compounds are, forexample, cited in Wagner and look, Synthetic Organic Chemistry, Wiley,New York (1953); acetals page 268; ketals page 273; aldehydespage 298;and ketones page 352.

After the treatment is effected, the desired product (formula llla) canbe separated by any suitable procedure, for example, extraction,evaporation, crystallization, chromatography and recrystallization.

The compounds of formula III wherein R and R form, together with thecarbon atom to which they are joined, an oxygen containing heterocyclicring can be more conveniently prepared by treating the correoverallreaction equation:

lIIh

wherein R is lower alkyl; n is a whole integer of from one through 4(i.e., n is l or 2), and R is as defined hereinabove.

The treatment is typically conducted by contacting the2-hydroxy-5-phenyl-benzyl alcohol of formula (D) with the O-alkylalkanoic acid lactonium tetrafluoroborate of formula (F), in thepresence of a suitable base, and preferably is conducted in a liquidinert organic reaction media. The treatment is typically conducted attemperatures in the range of about from 0 to 30C for about from 5minutes to 5 hours. However, treatment temperatures and times both aboveand below these ranges can also be used. The reagents can be contactedand maintained in any convenient order or fashion and preferably thetreatment is conducted under anhydrou conditions. After the treatment,the desired product (formula llla) can be separated and isolated fromthe reaction mixture by any technique such as, for example, evaporation,filtration, decantation, extraction, chromatography, and the like.

Suitable liquid inert organic reaction media include those usuallyemployed in organic reactions such as, for example, aromatics, e.g.,benzene, toluene; ethers, e.g., dioxane, diethylether, and the like;and, preferably, the halogenated hydrocarbons, e.g., chloroform,methylene chloride, carbon tetrachloride, l ,2- dichloroethane,l,l-dichloroethane, and the like; either individually or mixturesthereof. Suitable base catalysts include, for example, ammonia; primaryalkylamines, e.g., methylamine, ethylamine, isopropylamine,n-propylamine, and the like; secondary alkylamines, e.g., dimethylamine,diethylamine, methylpropylamine, and the like; trialkylamines, e.g.,trimethylamine, triethylamine, and the like; and monocyclic heterocyclicamines, e.g., pyridine, collidine, piperidine, morpholine, and the like.I 1

The reaction consumes the reactants on the basis of one equivalent of2-hydroxy5-phenyl-ben zyl alcohol formula (D) per equivalent of theO-alkyl alkanoic acid lactonium tetrafluoroborate (formulatFl) Per 5equivalent of base. However, the relative amounts of the reactantsemployed are not critical, some of the desired product being preparedwhen employing any proportions thereof. Best results are typicallyobtained by using about from one to 5 equivalents of each of the 0-alkyl alkanoic acid lactonium tetrafluoroborate and base per equivalentof 2-hydroxy-5-phenyl-benzyl alcohol starting material.

The O-alkyl alkanoic acid lactonium tetrafluoroborate is prepared byreacting together a trialkyloxonium tetra-fluoroborate and an alkanoicacid lactone, preferably in liquid inert organic reaction media at fromabout to about 20C for about from 24 to 48 hours. This method is morecompletely described in Ber. 89, 2060 (1965), which is herebyincorporated by reference. The process for preparing the O-alkylalkanoic acid lactonium tetrafluoroborate is also preferably conductedunder anhydrous conditions.

The compounds of my invention exhibit analgesic activity, in mammals,and thus are useful in alleviating or mitigating headaches, muscularaches and pains, and the like, occurring in mammals, and also fortemporary relief or mitigation of pain associated with conditions suchas arthritis, rheumatism, bursitis, and the like. The compounds of myinvention also exhibit both antipyretic and anti-inflammatory activityin mammals and thus are useful in reducing or combating fever and/orinfiamation in mammals. The compounds of my invention are typicallyadministered in dosages in the range of about from 50 to 2,000 mg. perday per 150 pounds of mammal weight. The compounds are preferablyadministered orally in any pharmaceutically suitable form for oraladministration. Thus, for example, the compounds can be administered aspills, either as the sole ingredient of a pill or in conjunction withsuitable pharmaceutical carriers or excipients and binders, and can alsobe combined with other pharmaceutically compatible pharmaceuticallyactive agents.

A further understanding of the invention can be had from the followingillustrative nonlimiting examples; wherein all molar and equiv. etc.,quantities refer to gram quantities.

. EXAMPLE 1 This example illustrates methods of preparing -(4-lower-alkyl-phenyl)-2-hydroxy-benzoic acid starting materials. in thisexample, 1.2 g. molar equivalents of lithium dimethyl copper in 50 ml.of tetrahydrofuranether (1:1 by vol.) is added to a solution of 5 g. of5-(4- iodophenyl)-2-acetoxy-methylbenzoate in 100 ml. of tetrahydrofuranat room temperature (i.e., about C). The reaction mixture is allowed tostand for 24 hours and then washed with water, dried over sodium sulfateand evaporated affording a residue of crude 5-(4-methylphenyl)-2-acetoxy-methylbenzoate, which is then furtherpurified by chromatography over neutral alumina and crystallizationusing an acetone-hexane solvent.

One gram of the purified product is added to 25 ml. of ethanol and thenmixed and boiled with an excess of sodium hydroxide for'six hours. Thismixture is then allowed to cool to room temperature (i.e., about 20C)and acidified by the addition of an excess of 1N aqueous hydrochloricacid to a pH of l. 100 Ml. ofwater are then added affording aprecipitate of 5-(4- methylphenyl)-2-hydroxy-benzoic acid which is thenrecovered by filtration, washed with water until neutral and then dried.

By following the same procedure, but respectively replacing lithiumdimethyl copper with lithium diethyl copper and lithium dipropyl copper,the starting materials 5-(4-ethylphenyl)-2-hydroxy-benzoic acid and 5-tively prepared.

EXAMPLE 2 This example illustrates methods of preparing 5-(4-trifluoromethyl)-2-hydroxy-benzoic acid starting materials. [n thisexample, 1 g. of 5-(4-iodophenyl)-2- acetoxy-methylbenzoate is dissolvedin 50 ml. of dimethylformamide in a steel bomb. 3 g.-molar equivalentsof iodotrifluoromethane gas is condensed in this solution by cooling to40C. Two grams of powdered copper is then added and the bomb sealed andheated to 140C and maintained at this temperature for 5 hours. Themixture is then allowed to cool to room temperature (i.e., about 20C)and the bomb then vented to relieve pressure. The reaction mixture isthen filtered to remove the powdered copper and poured into 200 ml. ofwater and extracted with three times 100 ml. aliquots of ethyl acetate.The ethyl acetate extracts are combined and evaporated to drynessaffording crude 5-(4-trifluoromethylphenyl)-2-acetoxymethylbenzoatewhich is then further purified by chromatography over neutral aluminaand crystallization using an acetone-hexane solvent. I

One gram of the purified product is added to 25 ml. of ethanol and thenmixed and boiled with an excess of sodium hydroxide for six hours. Thismixture is then allowed to cool to room temperature (i.e., about 20C)and acidified by the addition of an excess of 1N aqueous hydrochloricacid to a pH of l. 100 Ml. of water are then added affording aprecipitate of 5-(4- trifluoromethylphenyl)-2-hydroxy-benzoic acid whichis then recovered by filtration, washed with wateruntil neutral and thendried;

EXAMPLE 3 This example illustrates methods'of preparing 5-(4-lower-alkoxyphenyl)-2-hydroxy-benzoic acid starting materials. In thisexample an aqueous solution of 0.1 moles of sodium nitrile in. 20 ml. ofwater is slowly added dropwise to a constantly stirred mixture of 0.1moles of 5-(4-aminophenyl)-2-hydroxymethylbenzoate in 60 ml. of 6Naqueous sulfuric acid (which is prepared by the addition of5-(4-aminophenyl)-2- hydroxymethylbenzoate to the sulfuric acid solutionat 0C) at 5C. The resulting mixture is constantly stirred and maintainedat 5C for an additional hour and then added to a boiling solutioncontaining 10 ml. of concentrated sulfuric acid and ml. of water. Themixture is boiled for an additional 5 minutes and then allowed to coolto room temperature and then further cooled to about 7C and stored atthis temperature for 8 hours, resulting in the crystallization of acrude'intermediate product which is recovered by filtration-One gram ofthis intermediate is dissolved in 30 ml. of a 1:1 (by vol.) mixture ofmethanoland water at roo m'temperature (i.e., about 20C). Twoequivalents of a l percent aqueous potassium hydroxide solution is thenadded to this solution, followed by the addition of 2 equiv. ofdimethyl'sulfa'te. The resulting mixture is stirred at room temperaturefor 2 hours-and then extracted with ethyl acetate. The ethylacetate'extract is washed with water and then evaporated affording acrude 5-( 4-methoxyphenyl )-2 -hydroxymethylbenzoate residue which isfurther purified by chromatography on silica gel followed byrecrystallization from amethylene chloridezether solvent mixture.

One gram of the above product is heated for 1 hour at reflux in 50 ml.of a 2 percent potassium hydroxidemethanol solution containing a traceof water and then cooled and evaporated. 100 Ml. of water are then addedto the residue followed by the addition of 5 ml. of concentrated aceticacid. The acidified mixture is then extracted with ethyl acetate and theresulting ethyl acetate extracts evaporated to dryness affording a crude5-(4-methoxyphenyl)-2-hydroxy-benzoic acid residue which is furtherpurified by chromatography over neutral alumina.

Similarly, 5-(4-ethoxyphenyl)-2-hydroxy-benzoic acid is prepared byfollowing the same procedure but using diethylsulfate in place ofdimethylsulfate.

EXAMPLE 4 This example illustrates methods according to my invention ofpreparing the 6-phenyl-l,3-benzodioxan- 4-one compounds of formula II ofmy invention. In this example 2.3 ml. (15 mmoles) of triethylorthoformate is added dropwise to a solution of 2.3 g. (10 mmoles) of5-(4'-fluorophenyl)-2-hydroxybenzoic acid and 2 mg. of p-toluenesulfonicacid in 50 ml. of benzene. The mixture is then refluxed for 4 hours,then allowed to cool to room temperature and neutralized by the additionof 50 ml. of aqueous 10 percent sodium carbonate solution. The organicphase is then separated, washed three times with 50 m1. aliquots ofwater and then evaporated to dryness. The resulting residue is furtherpurified by chromatography affording 2-ethoxy-6-(4'- fluorophenyl)-l,3-benzodioxan-4-one.

By following the same procedure as above but using the corresponding2-hydroxy-5-phenyl-benzoic acid derivatives as starting materials, thefollowing compounds are prepared:

6-(4-chlorophenyl)-2-ethoxy-l ,3-benzodioxan- 4-one;

6-( 4 -bromophenyl)-2-ethoxyl ,3-benzodioxan- 4-one;

2-ethoxy-6-(4-iodophenyl)-l ,3-benzodioxan-4-one;

2-ethoxy-6-phenyl-l ,3-benzodioxan-4-one;

2-ethoxy-6-(4-trifluoromethylphenyl)-l ,3-benzodioxan-4-one;

2-ethoxy-6-(4'-methylphenyl)- 1 ,3-benzodioxan- 4-0ne; and

2-ethoxy-6-( 4 -methoxyphenyl)-1,3-benzodioxan- 4-one.

By following the same procedure but using trimethylorthoformate in placeof triethylorthoformate, the following compounds are respectivelyprepared:

6-(4'-fluorophenyl )-2-methoxy-l ,3-benzodioxan- 4-one;

6-( 4-chlorophenyl)-2-methoxy-l ,3-benzodioxan- 4-one;

6-( 4-bromophenyl )-2-methoxyl ,3-benzodioxan- 4-one;

6-(4-iodophenyl)-2-methoxy-l ,S-benzodioxan- 4-one;

2-methoxy-6-phenyl-l ,3-benzodioxan-4-one;

2-methoxy-6-(4'-trifluoromethylphenyl)-1,3-benzodioxan-4-one;

2-methoxy-6-( 4 '-methylphenyl)-1,3-benzodioxan- 4-one; and

2-methoxy-6-( 4 '-methoxyphenyl)-1,3-benzodioxan- By following the sameprocedure but using triethylorthopropionate in place oftriethylorthoformate, the following compounds are respectively prepared:

2-ethoxy-2-ethyl-6-( 4-fluorophenyl)- l ,3-benzodioxan-4-one;

6-(4'-chlorophenyl)-2-ethoxy-2-ethyll ,3-benzodioxan-4-one;

6-(4'-bromophenyl)-2-ethoxy-2-ethyll ,3-benzodioxan-4-one;2-ethoxy-2-ethyl-6-(4'-iod0phenyl)-l ,3-benzodioxan-4-one;

2-ethoxy-2-ethyl-6-phenyl-l ,3-benzodioxan-4-one;

benzodioxan-4-one; v 2-ethoxy-2 ethyl-6-( 4'-methylphenyl)-l,3-benzodioxan-4-one; and

2-ethoxy-2-ethyl-6-( 4'-methoxyphenyl)-l ,3-benzodi-' oxan-4-one.

By following the same procedures as above but usingtrimethylorthovalerate in place of triethylorthoformate, the followingcompounds are respectifully prepared:

2-butyl-6-( 4' -fluorophenyl )-2-methoxyl ,3-benzodioxan-4-one;2-butyl-6-(4-chlorophenyl)-2-methoxy-l ,3-benzodioxan-4-one;6-(4-bromophenyl)-2-butyl-2-methoxy-1,3-benzodioxan-4-one;

2-butyl-6-( 4'-iodophenyl)-2-methoxyl ,3-benzodioxan-4-one;2-butyl-2-methoxy-6-phenyl-1,3-benzodioxan-4-one;

2-butyl-2-methoxy-6-(4-trifluoromethylphenyl)-l ,3-

benzodioxan-4-one; 2-butyl-2-methoxy-6-(4'-methylphenyl)-l,3-benzodioxan-4-one; and 2-butyl-2-methoxy-6-(4'-methoxyphenyl)- l,3-benzodioxan-4-one.

EXAMPLE 5 This example illustrates further methods according to myinvention of preparing the 6-phenyl-l,3-benzodioxan-4-one compounds offormula II of my invention. In this example 4.2 g. of ethoxy acetylenein 25 ml. of dichloromethane is added dropwise over a period of 15minutes to 6.95 g. of 5-(flu0rophenyl)-2-hydroxybenzoic acid in ml. ofdichloromethane containing 1 gram of mercuric acetate, in a dry ice andacetone bath. The dry ice and acetone bath is allowed to evaporate andthe mixture allowed to rise to room temperature (i.e., about 20C) over aperiod of three hours. The dichloromethane solvent is then removed byevaporation under vacuum. The resulting concentrate is then distilledaffording a distillate of crude 2-ethoxy-5- (4-fluorophenyl )-2-methyl-l,3-benzodioxan-4-one which is then further purified by thin-layerchromatography.

By following the same procedure as above but using the corresponding2-hydroxy-5-phenyl-benzoic acid derivatives as starting materials, thefollowing compounds are respectively prepared:

6-(4-chlorophenyl)-2-ethoxy-2-methyl-1,3-benzodioxan-4-one; I6-(4'-bromophenyl)-2-ethoxy-2-methyll ,3-benzodioxan-4-one; v

2-ethoxy-6-( 4'-iodophenyl)-2methyll ,3benzodioxan-4-one;

2-ethoxy-2-methyl-6-phenyl l ,3-benzodioxan-4-one;

17 2-ethoxy-6-( 4'-trifluoromethylphenyl )-2-ethyll ,3-

benzo-dioxan-4-one; 2-ethoxy-2-methyl-6-(4-methylphenyl)- l,3-benzodioxan-4-one; and2-ethoxy-6-(4'-methoxyphenyl)-2-methyl-1,3-benzodioxan-4-one.

By following the same procedure but using 4-ethoxy- 3 butyne in place ofethoxy-acetylene, the following compounds are respectively prepared:

2-ethoxy-6-(4-fluorophenyl)-2-propyl-l ,3-benzodioxan-4-one;

6-( 4 -chlorophenyl )-2-ethoxy-2-propyll ,3-benzodioxan-4-one;6-(4-bromophenyl)-2-ethoxy-2-propyll ,3-benzodioxan-4-one;

2-ethoxy-6-(4-iodophenyl)-2propyl-l ,3-benzodioxan-4-one;2-ethoxy-6-phenyl-2-propyll ,3-benzodioxan-4-one;

2-ethoxy-2-propyl-6-( 4-trifluoromethylphenyl)-l ,3-

benzodioxan-4-one; 2-ethoxy-6- (4'-methylphenyl)-2-propyl-l,3-benzodioxan-4-one', and

2-ethoxy-6-( 4'-methoxyphenyl )-2-propyll ,3-benzodioxan-4-one.

By following the same procedure as above but using 8-heptyloxy-7-octynein place of ethoxy-acetylene, the following compounds are respectivelyprepared:

6-(4'-fluorophenyl)-2-heptyl-2-heptyloxy-l ,3-benzodioxan-4-one;

6-( 4'-chlorophenyl)-2-heptyl-2-heptyloxyl ,3-benzodioxan-4-one;

6-( 4'-bromophenyl )-2-heptyl-2-heptyloxy-l ,3-benzodioxan-4-one;2-heptyl-2-heptyloxy-6-(4'-iodophenyl)-l ,3-benzodioxan-4-one;2-heptyl-2-heptyloxy-6-(4-trifluoromethylphenyll,3-benzodioxan-4-one;2-heptyl-2-heptyloxy-6-(4-methylphenyl)-l ,3-benzodioxan-4-one; and2-heptyl-2-heptyloxy-6-(4-methoxyphenyl)-l ,3benzodioxan-4-one.

EXAMPLE 6 This example illustrates methods of preparing the2-hydroxy-5-phenyl-benzyl alcohol starting materials of formula (D) bythe reduction of the corresponding 2-hydroxy-5-phenyl-benzoic acids. Inthis example 0.57 g. (lmmoles) of powdered lithium aluminum hydride in 5ml. of tetrahydrofuran is slowly added over a period of ten minutes to arefluxing mixture of 4.64 (20 mmoles) of5-(4'-fluorophenyl)-2-hydroxy-benzoic acid in ml. of tetrahydrofuran ina reflux apparatus having a remote vent to permit the escape ofbyproduct hydrogen released by the reaction. The resulting mixture isthen refluxed for an additional two hours and then cooled to 50C andconcentrated to a volume of 15 ml. by vacuum evaporation. Theconcentrate is treated in an excess of acetone and then hydrolyzed bythe addition of 5 ml. of water at 40C and allowed to cool to and standat 40C for minutes and then further concentrated to a volume of 11 ml.by vacuum evaporation. The l 1 ml. concentrate is cooled to roomtemperature (i.e., about 20C), then filtered and the resulting filtratesuccessively extracted with five 5 ml. portions of benzene. The benzeneextracts are then combined and evaporated to dryness affording a residueof crude 5-(4'-fluorophenyl)-2-hydroxy-benzyl alcohol, which is furtherpurified by thin-layer chromatography.

Similarly by following the same procedure as above but using thecorresponding S-position phenyl benzoic acid derivatives as startingmaterials, the following compounds are respectively prepared:

5-(4'-chlorophenyl)-2-hydroxyl-benzyl alcohol;

5-(4-bromophenyl)-2-hydroxyl-benzyl alcohol;2-hydroxyl-S-(4-iodophenyl)-benzyl alcohol; 2-hydroxyl-5-phenyl-benzylalcohol; 2-hydroxyl-5-(4'-trifluoromethylphenyl)-benzyl cohol;2-hydroxyl-5-(4'-methylphenyl)-benzyl alcohol; and2-hydroxyl-5-(4'-methoxyphenyl)-benzyl alcohol.

EXAMPLE 7 This example illustrates methods according to my invention ofpreparing the 2-alkoxy compounds of formula III of my invention. In thisexample 2.3 ml. (15 mmoles) of triethyl orthoformate is added dropwiseto a solution of 2.18 g. 10 mmoles) of 5-(4'-fluorophenyl)-2-hydroxy-benzyl alcohol and 2 mg. of p-toluenesulfonic acid in 50 ml.of benzene. The mixture is then re fluxed for 4 hours, then allowed tocool to room temperature and neutralized by the addition of 50 ml. ofaqueous 10 percent sodium carbonate solution. The organic phase is thenseparated, washed three times with 50 ml. aliquots of water and thenevaporated to dryness. The resulting residue is further purified bychromatography affording 2-ethoxy-6-(4-fluorophenyl)- l ,3-benzodioxane.

By following the same procedure as above but using the .corresponding2-hydroxy-5-phenyl benzyl alcohol derivatives as starting materials, thefollowing compounds are prepared:

6-( 4'-chlorophenyl)-2-ethoxyl ,3-benzodioxane;

6-(4-bromophenyl)-2-ethoxy-l ,3-benzodioxane;

2-ethoxy-6-(4-iodophenyl)-l ,3-benzodioxane; 2-ethoxy-6-phenyl-l,3-benzodioxane;

2-ethoxy-6-( 4'-trifluoromethylphenyl) l ,3-

benzodioxane;

2-ethoxy-6-(4'-methylphenyl I ,3-benzodioxane;

and

2-ethoxy-6-(4-methoxyphenyl)- l ,3-benzodioxane.

By following the same procedure but using trimethylorthoformate in placeof triethylorthoformate, the following compounds are respectivelyprepared:

6-(4-fluorophenyl)-2-methoxyl ,3-benzodioxane;

6-( 4'-chloropheny1)-2-methoxyl ,3-benzodioxane;

6-( 4'-bromophenyl)-2-methoxyl ,3-benzodioxane;

6-( 4-iodophenyl)-2-methoxy-l ,3-benzodioxane;

2-methoxy-6-phenyll ,3-benzodioxane;

2-methoxy-6-(4'-trifluoromethylphenyl )-l ,3-

benzodioxane; v 2-methoxy-6-(4-methylphenyl)- l ,3-benzodioxane;

and

2-methoxy-6-(4'- methoxyphenyl)-1,3-benzodioxane.

By following the same procedure but using triethylorthopropionate inplace of triethylorthoformate, the folbenzodioxane;

2-ethoxy-2-ethyl-6-phenyll ,3-benzodioxane;

2-ethoxy-2-ethy1-6-( 4-trifluoromethylyphenyl l ,3-

benzodioxane;

2-ethoxy-2-ethyl-6-(4-methylphenyl)-l ,3-

benzodioxane; and 2-ethoxy-2-ethyl-6-(4-methoxyphenyl)-1,3-

benzodioxane.

By following the same procedures as above but usingtrimethylorthovalerate in place of triethylorthoformate, the followingcompounds are respectfully prepared:

2-butyl-6-(4-fluorophenyl)-2-methoxy-l ,3-

benzodioxane; 2-butyl-6-(4-chlorophenyl)-2-methoxy-1,3-

benzodioxane;

6-( 4 -bromophenyl)-2-butyl-2-methoxy l ,3-

benzodioxane;

2-butyl-6-(4-iodophenyl)-2-methoxy-l ,3-

benzodioxane;

2-butyl-2-metho'xy-6-phenyl-l ,3-benzodioxane;

2-butyl-2-methoxy-6-( 4-trifluoromethylphenyl 1 ,3-

benzodioxane;

2-butyl-2-methoxy-6-(4'-methylphenyl)-l ,3-

benzodioxane; and

2-butyl-2-methoxy-6-(4-methoxyphenyl)-l ,3-

benzodioxane.

EXAMPLE 8 This example illustrates further methods according to myinvention of preparing 2-alkoxy compounds of formula III of myinvention. In this example 4.2 g. of ethoxy acetylene in 25 ml. ofdichloromethane is added dropwise over a period of minutes to 6.53 g. of5- (fluorophenyl)-2-hydroxy-benzyl alcohol in 75 ml. of dichloromethanecontaining 1 gram of mercuric acetate, in a dry ice and acetone bath.The dry ice and acetone bath is allowed to evaporate and the mixtureallowed to rise to room temperature (i.e., about C) over a period ofthree hours. The dichloromethane solvent is then removed by evaporationunder vacuum. The resulting concentrate is then distilled affording adistillate of crude 2-ethoxy-5-(4-fluorophenyl)-2- methyl-l,3-benzodioxane which is then further purified by thin-layerchromatography.

By following the same procedure as above but using the corresponding2-hydroxy-5-phenyl-benzyl alcohol derivatives as starting materials, thefollowing compounds are respectively prepared:

6-(4-chlorophenyl)-2-ethoxy-2-methyl-l ,3-

benzodioxane;

6-(4'-bromophenyl)-2-ethoxy-2-methyl-l ,3-

benzodioxane;

2-ethoxy-6-(4-iodophenyl)-2-methyl-l ,3-

A benzodioxane;

2-ethoxy-2-methyl-6-phenyl-l ,3-benzodioxane;

2-ethoxy-6-(4"trifluoromethylphenyl)-2-ethyll,3benzo-dioxane;

2-ethoxy-2-methyl-6-(4-methylphenyl)- l ,3-

benzodioxane; and 2-ethoxy-6-(4-methoxyphenyl)-2-methyl-1,3-

benzodioxane..

By following the same procedure but using 4-ethoxy- 3-butyne in place ofethoxy-acetylene, the following compounds are respectively prepared:

2-ethoxy-6-(4 -fluorophenyl )-2-propyll ,3-

benzodioxane;

6-( 4-chlorophenyl)-2-ethoxy-2-propyll ,3-

benzodioxane;

6-(4'-bromophenyl)-2-ethoxy-2propyl-l ,3-

benzodioxane;

2-ethoxy-6-( 4-iodophenyl )-2-propyll ,3-

benzodioxane; 2-ethoxy-6-phenyl-2-propyl-1,3-benzodioxane;

2-ethoxy-2-propyl-6-( 4-trifluoromethylphenyl)-l ,3-

benzo-dioxane;

2-ethoxy-6-( 4'-methylphenyl )-2-propyl-l ,3-

benzodioxane; and

2-ethoxy-6-(4'-methoxyphenyl )-2-propyll ,3-

benzodioxane.

By following the same procedure as above but using 8-heptyloxy-7-octynein place of ethoxy-acetylene, the following compounds are respectivelyprepared:

benzodioxane;

6-( 4'-chlorophenyl)-2-heptyl-2-heptyloxy-l ,3-

benzodioxane;

6-( 4'-bromophenyl )-2-heptyl-2-heptyloxy-1 ,3-

benzodioxane;

2-heptyl-2-heptyloxy-6-( 4'-iodophenyl )-l ,3-

benzodioxane; 2-heptyl-2-heptyloxy-6-phenyll ,3-benzodioxane;2-heptyl-2-heptyloxy-6-( 4'-trifluoromethylphenyl 1,3-benzodioxane;

2-heptyl-2-heptyloxy-6-( 4-methylphenyl)-l ,3-

benzodioxane;

2-heptyl-2-heptyloxy-6-( 4'-methoxyphenyl l ,3-

benzodioxane; and

6-(4'-diphenyl)-2-heptyl-2-heptyloxy-l ,3-

benzodioxane.

EXAMPLE 9 This example illustrates methods according to my invention ofpreparing the compounds of formula III of my invention. In this example0.5 grams of 5-(4- fluorophenyl)-2-hydroxybenzy1 alcohol and 0.1 ml. ofpercent perchloric acid are respectively added to 10 ml. of acetone. Theresulting mixture is stirred for 8 hours at room temperature (i.e.,about20C) and then neutralized by the addition of 10 ml. of distilledwater containing 0.5 g. of sodium bicarbonate. The mixture is thenconcentrated by vacuum evaporation to remove excess acetone, resultingin a precipitate which is then recovered by filtration. The precipitateis then further.

Similarly, by following the same procedure but using diisopropyl ketonein place of acetone, the following compounds are respectively prepared:

6-( 4'-fluorophenyl )-2,2-diisopropyll ,3-

benzodioxane;

6-( 4 '-chlorophenyl) 2,2-diisopropyl-1,3-

benzodioxane;

6-('4'-bromophenyl )-2,2-diisopropyl-l ,3-

benzodioxane; 6-(4-iodophenyl)-2,2-diisopropyl-1,3-

benzodioxane;

2-diisopropyl-6-phenyl-l ,3-benzodioxane;

2,2-diisopropyl-6-( 4'-trifluoromethylphenyl)- l ,3-

benzodioxane; 2,2-diisopropyl-6-(4'-methylphenyl)-1,3-

benzodioxane; and

2,2-diisopropyl-6-(4-methoxyphenyl)-l ,3-

benzodioxane.

By following the same procedure as above but using ethyl n-hexyl ketonein place of acetone, the following compounds are prepared:

2-ethyl-6-(4'-fluorophenyl)-2-n-hexyl-l ,3-

benzodioxane;

6-( 4'-chlorophenyl)-2-ethyl-2-n-hexyll ,3-

benzodioxane; 6-(4-bromophenyl)-2-ethyl-2-n-hexyl-1,3-

benzodioxane;

benzodioxane;

2-ethyl-2-n-hexyl-6-phenyl-l ,3-benzodioxane;

2-ethyl-2-n-hexyl-6(4-trifluoromethylphenyl l ,3-

benzodioxane;

2-ethyl-2-n-hexyl-6-(4'-methylphenyl)-l ,3-

benzodioxane; and

2-ethyl-2-n-hexyl-6-(4'-methoxyphenyl)-l ,3-

benzodioxane.

EXAMPLE 10 This example illustrates methods according to my invention ofpreparing the compounds of formula III of my invention. In this example5.2 ml. (50 mmoles) of cyclohexanone is added to a mixture containing4.36 g. (20 mmoles) of -(4-fluoro-phenyl)-2-hydroxy-benzyl alcohol and20 mg. of p-toluene-sulfonic acid in 100 ml. of benzene. The mixture isrefluxed for four hours and then neutralized by the addition of ml. of10 percent (by weight) aqueous potassium carbonate solution. Theneutralized mixture is then concentrated by vacuum evaporation to removeany benzene solvent. The concentrate is then subjected to thin-layerchromatography affording crude 6-(4'-fluorophenyl)-l,3-benzodi0xane-2-spiro-cyclohexane which is then further purified byrecrystallization using ether-hexane.

By following the same procedure as above but using the corresponding2-hydroxy-S-phenyl-benzyl alcohol derivatives as starting materials, thefollowing compounds are respectively prepared:

6-(4'-chlorophenyl)-l ,3-benzodioxane-2-spirocyclohexane;

6-( 4 -bromophenyl)- l ,3-benzodioxane-2-spirocyclohexane;

6-( 4 '-iodophenyl l ,3-benzodioxane-2-spirocyclohexane;

6-phenyl-l ,3-benzodioxane-2-spiro-cyclohexane;

6-( 4'-trifluoromethylphenyl)-l ,3-benzodioxane-2- spiro-cyclohexane;

22 6-(4-methylphenyl )-l ,3-benzodioxane-2-spirocyclohexane; and6-(4-methoxyphenyl)-1,3-benzodioxane-2-spirocyclohexane.

Similarly, by following the same procedure but usingtetrahydrothiophen-3-one in place of cyclohexanone, the followingcompounds are respectively prepared:

' 6-(4-fluorophenyl)- l ,3-benzodioxane-2-spiro-3 tetrahydrothiophene;'6-(4-chlorophenyl)- l ,3-benzodioxane-2-spiro-3 tetrahydrothiophene;6-(4-bromophenyl)-1,3-benzodioxane-2-spiro-3 tetrahydrothiophene;6-(4-iodophenyl)- l ,3-benzodioxane-2-spiro-3 tetrahydrothiophene;'o-phenyll ,3-benzodioxane-2-spiro-3 -tetrahydrothiophene; 6-(4-trifluoromethylphenyl)-l ,3-benzodioxane-2-spire-3-tetrahydrothiophene; 6-(4-methylphenyl)- l,3-benzodioxane-2-spiro-3 tetra-hydrothiophene; and 16-(4-methoxyphenyl)-1,3-benzodioxane-2-spiro-3 tetra-hydrothiophene.

EXAMPLE 1 1 This example illustrates further methods according to myinvention of preparing the compounds of formula III of my invention. Inthis example 5.8 ml. (50 mmoles) of 2,2-diethoxypropane is added to 4.36g. (20 mmoles) of 5-(4-fluorophenyl)-2-hydroxy-benzyl alcohol and mg. ofp-toluenesulfonic acid in 100 ml. of benzene. The mixture is thenrefluxed for 6 hours in a soxhlet apparatus (containing 4 g. of 13Xmolecular sieve zeolite beads to remove by-product ethanol) and thenallowed to cool to room temperature. The cooled mixture is thenneutralized by the addition of 200 mg. of sodium bicarbonate. Theneutralized mixture is then evaporated to dryness and the resultingresidue redissolved in a mixture of methylene chloride and ether (9:1,by volume), then filtered. The filtrate is then subjected to thin-layerchromatography affording crude 6-(4'-fluoro-phenyl)-2,2 dimethyl-l ,3-benzodioxane which is then further purified by recrystallization usingacetone-hexane as solvent.

By following the same procedure as above but using the corresponding2-hydroxy-S-phenyl-benzyl alcohol starting materials, the followingcomponds are respectively prepared: 1

6-( 4-chlorophenyl )-2,2-dimethyl-l ,3-benzodioxane;

6-( 4-bromopheny1)-2,2-dimethyll ,3-benzodioxane;

6-(4'-iodophenyl )-2,2-dimethyli ,3-benzodioxane;

6-phenyl-2,2-dimethyl-l ,3-benzodioxane;

benzodioxane;

2,2-dimethyl-6-(4-methylphenyl)-l ,3-

benzodioxane; and

6-(4'-methoxyphenyl)-2,2-dimethyl-l ,3-

benzodioxane.

Similarly, by following'the-same procedure but using l,l-dimethoxycyclope'ntane in place of 2,2-dimethoxypropane, the following compoundsare respectively prepared:

cyclopentane;

6-( 4-chlorophenyl l ,3 benzodioxane-2-spirocyclopentane; I 1

6-(4'-bromophenyl l ,3-benzodioxane-2-spirocyclopentane;

6-(4-iodophenyl)-l ,3-benzodioxane-2-spirocyclopentane;

6-phenyll ,3-benzodioxane-2-spiro-cyclopentane; 5

6-( 4-trifluoromethylphenyl)- l ,3-benzodioxane-2- spiro-cyclopentane;

6-(4-methylphenyl)-l ,3-benzodioxane-2-spirocyclopentane; and

6-( 4'-methoxyphenyl)- l ,3-benzodioxane-2-spirocyclopentane.

Similarly, by following the same procedure but using4-methyl-l,l-dimethoxy-cycloheptane in place of 2,2-dimethoxypropane,the following compounds are respectively prepared:

6-(4-fluorophenyl)-l ,3-benzodioxane-2-spiro-l (4-methylcycloheptane);6-(4'-chlorophenyl)-l,3-benzodioxane-2-spiro-1'-(4'-methylcycloheptane); 6-(4-bromophenyl l ,3benzodioxane-2-spiro-l(4'-methylcycloheptane); 6-(4'-iodophenyl l ,3-benzodioxane-2-spiro-l'-(4- methylcycloheptane);6-phenyl-l,3-benzodioxane-2-spiro-1'-(4-methylcyclo-heptane);

6-(4-trifluoromethylphenyl)-l ,3-benzodioxane-2- spiro-l-(4'-methylcycloheptane);

6-( 4-methylphenyl)-l ,3-benzodioxane-2-spiro-l (4-methylcycloheptane);and

6-(4-methoxyphenyl)-l ,3-benzodioxane-2-spiro-l (4-methylcycloheptane).

EXAMPLE 12 This example illustrates methods for preparing 0- alkylalkanoic acid lactonium tetrafluoroborate cornpounds useful in thepreparation of the compounds of formula lllb of my invention. In thisexample, one gram of triethyloxonium tetrafluoroborate is dispersed in 5ml. of dry methylene chloride under a nitrogen atmosphere. To theresultant mixture is added 0.45 ml. of butyric acid lactone whilemaintaining the anhydrous conditions. The resultant mixture is allowedto stand overnight at room temperature to provide a solution of O-ethylbutyric acid lactonium tetrafluoroborate.

In accordance with the foregoing procedure, the alkanoic acid lactoneslisted in Column A below are respectively reacted with eachtrialkyloxonium tetrafluoroborates listed in Column B below to providethe respective reagents listed under Column C below.

Column A ColumB butyric acid trimethyloxonium lactone tetrafluoroboratepentanoic acid triethyloxonium lactone tetrafluoroborate hexanoic acidtri-n-propyloxonium lactone tetrafluoroborate heptanoic acid lactoneCOLUMN C O-methyl butyric acid lactonium tetrafluoroborate; 6O O-ethylbutyric acid lactonium tetrafluoroborate; O-n-propyl butyric acidlactonium tetrafluoroborate; O-methyl pentanoic acid lactoniumtetrafluoroborate; O-ethyl pentanoic acid lactonium tetrafluoroborate;O-n-propyl pentanoic acid lactonium tetrafluoroborate;

O-methyl hexanoic acid lactonium tetrafluoroborate;

O-ethyl hexanoic acid lactonium tetrafluoroboratc;

O-n-propyl hexanoic acid lactonium tetrafluoroborate;

O-methyl heptanoic acid lactonium tetrafluoroborate;

O-ethyl heptanoic acid lactonium tetrafluoroborate;

and

O-n-propyl heptanoic acid lactonium tetrafluoroborate.

EXAMPLE 13 This example illustrates methods according to my invention ofpreparing the compounds of formula IlIb of my invention. In thisexample, 3.5 ml. of a solution of O-ethyl butyric acid lactoniumtetrafluoroborate prepared according to Example 12 is added dropwiseover a period of 10 minutes to a mixture of 2.18 g. of 5-(4'-fluorophenyl)-2-hydroxybenzyl alcohol and 2.8 ml. of anhydroustriethylamine in 25 ml. of anhydrous methylene chloride, at roomtemperature, with constant stirring. The resulting mixture is aged atroom temperature (i.e., about 20C) with constant stirring for 30minutes, and then filtered through a column of alumina. The filtrate isthen crystallized affording 6-(4'-phenyl)-l ,3-benzodioxane-Z-spiro-Z-tetrahydrofuran, which is then further purifiedby thin-layer chromatography.

By following the same procedure above but using the corresponding2-hydroxy-5-phenyl-benzyl alcohol as starting materials, the followingcompounds are respectively prepared:

6-( 4-chlorophenyl l ,3-benzodioxane-2-spiro-2 tetrahydrofuran;

6-(4'-bromophenyl)-l ,3-benzodioxane-2-spiro-2- tetrahydrofuran;

6-(4-iodophenyl)-l ,3-benzodioxane-2-spiro-2'- tetrahydrofuran;

6-phenyll ,3-benzodioxane-2-spiro-2 tetrahydrofuran;6-(4-trifluoromethylphenyl)-1,3-benzodioxane-2-Spiro-2'-tetrahydrofuran;

6-(4-methylphenyl)-l ,3-benzodioxane-2-spiro-2'- tetrahydrofuran; and

6-(4-methoxyphenyl)-l ,3-benzodioxane-2-spiro-2'- tetrahydrofuran.

Similarly, by following the same procedure but using O-methyl pentanoicacid lactonium tetrafluoroborate in place of of O-ethyl butyric acidlactonium tetrafluoride, the following compounds are respectivelyprepared:

6-(4-fluorophenyl)-l ,3-benzodioxane-2-spiro-2'- tetrahydropyran;

6-(4-chlorophenyl)-l ,3-benzodioxane-2-spiro-2'- tetrahydropyran;

6-( 4'-bromophenyl l ,3-benzodioxane-2-spiro-2 tetrahydropyran;

6-(4-iodophenyl)-l ,3-benzodioxane-2-spiro-2-tetra-hydropyran;6-phenyl-l ,3-benzodioxane-2-spiro-2 -tetrahydr0pyran;6-(4-trifluoromethylphenyl)-1,3-benzodioxane-2-spire-2'-tetrahydropyran;

6-( 4'-methylphenyl l ,3-benzodioxane-2-spiro-2 tetra-hydropyran; and

6-( 4'-methoxyphenyl)-l ,3-benzodioxane-2-spiro-2 tetra-hydropyran.

Obviously many modifications and variations of the invention, described"Herein above and below, cah b e made without departing from the essenceand scope thereof.

What is claimed is:

1. A compound having the formula:

R1 R- 8 8a 1 r i 0 2 I 1 e 30 WWW wherein R is selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy, fluoro, chloro,bromo, iodo, and trifluoromethyl; R is selected from the groupconsisting of hydrogen and lower alkyl; and R is lower alkyl.

2. The compound of claim 1 wherein R is selected from the groupconsisting of fluoro, chloro, and trifluoromethyl.

is 6-(4-chlorophenyl)-2-ethoxy-2-methyl-l ,3-benzodioxan-4-one.

8. The compound of claim 1 wherein said compound is2-ethoxy-6-(4-trifluoromethylphenyl)-l ,3-benzodioxan-4-one.

9. The compound of claim 1 wherein said compound is 2-ethoxy-6-phenyl-l,3-benzodioxan-4-one.

2. The compound of claim 1 wherein R is selected from the groupconsisting of fluoro, chloro, and trifluoromethyl.
 3. The compound ofclaim 1 wherein R is fluoro.
 4. The compound of claim 1 wherein saidcompound is 2-ethoxy-6-(4''-fluorophenyl)-1,3-benzodioxan-4-one.
 5. Thecompound of claim 1 wherein said compound is6-(4''-chlorophenyl)-2-ethoxy-1,3-benzodioxan-4-one.
 6. The compound ofclaim 1 wherein said compound is2-ethoxy-6-(4''-fluorophenyl)-2-methyl-1,3-benzodioxan-4-one.
 7. Thecompound of claim 1 wherein said compound is6-(4''-chlorophenyl)-2-ethoxy-2-methyl-1,3-benzodioxan-4-one.
 8. Thecompound of claim 1 wherein said compound is2-ethoxy-6-(4''-trifluoromethylphenyl)-1,3-benzodioxan-4-one.
 9. Thecompound of claim 1 wherein said compound is2-ethoxy-6-phenyl-1,3-benzodioxan-4-one.